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Hindawi Publishing CorporationThe Scientific World JournalVolume 2013, Article ID 732340, 13 pageshttp://dx.doi.org/10.1155/2013/732340

Review ArticleDendrimeric Systems and Their Applications inOcular Drug Delivery

Burçin Yavuz, Sibel BozdaL Pehlivan, and NurGen Ünlü

Pharmaceutical Technology Department, Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey

Correspondence should be addressed to Sibel Bozdag Pehlivan; [email protected]

Received 7 August 2013; Accepted 9 September 2013

Academic Editors: A. Concheiro and J. M. Reid

Copyright © 2013 Burcin Yavuz et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Ophthalmic drug delivery is one of the most attractive and challenging research area for pharmaceutical scientists andophthalmologists. Absorption of an ophthalmic drug in conventional dosage forms is seriously limited by physiological conditions.The use of nonionic or ionic biodegradable polymers in aqueous solutions and colloidal dosage forms such as liposomes,nanoparticles, nanocapsules, microspheres, microcapsules, microemulsions, and dendrimers has been studied to overcome theproblems mentioned above. Dendrimers are a new class of polymeric materials. The unique nanostructured architecture ofdendrimers has been studied to examine their role in delivery of therapeutics and imaging agents. Dendrimers can enhance drug’swater solubility, bioavailability, and biocompatibility and can be applied for different routes of drug administration successfully.Permeability enhancer properties of dendrimers were also reported. The use of dendrimers can also reduce toxicity versus activityand following an appropriate application route they allow the delivery of the drug to the targeted site and provide desiredpharmacokinetic parameters.Therefore, dendrimeric drug delivery systems are of interest in ocular drug delivery. In this review, thelimitations related to eye’s unique structure, the advantages of dendrimers, and the potential applications of dendrimeric systemsto ophthalmology including imaging, drug, peptide, and gene delivery will be discussed.

1. Introduction

Drug delivery to the eye is still one of the most challengingtasks for pharmaceutical scientists. The eye is characterizedwith its complex structure with high resistance to drugs aswell as other foreign substances. The anterior and posteriorsegments of the eye function both independently upon anocular application [1]. Thus, ocular drug delivery can beclassified into anterior and posterior segments.

Conventional drug delivery systems are not effectiveenough to meet the requirements in the treatment of oculardiseases [2]. However, “more than 90% of the marketedophthalmic formulations” are in the form of eye drops, andmost of them target the “anterior segment eye diseases”[3]. Poor bioavailability of drugs from ocular dosage formsis mainly due to the “precorneal loss factors” includingsolution drainage, lacrimation, tear dynamics, tear dilution,tear turnover, conjunctival absorption, transient residencetime in the cul-de-sac, and low permeability of the corneal

epithelial membrane which are the major challenges to ante-rior segment drug delivery following topical administration.

Treatment of “posterior segment diseases” still remains asan unsolved issue.Most of the ophthalmic diseases affect neu-ral retina, choroid, and vitreous. For example, glaucoma, dia-betic retinopathy, age-related macular degeneration (AMD),and various forms of retinitis pigmentosa are damaging theposterior eye segment, which may cause impaired visionand even blindness [4]. Delivery of drugs to the posteriorsegment is more challenging than to the anterior segment,due to the acellular nature of the vitreous body and the longerdiffusion distance [5]. Thus, posterior eye segment diseaseshave become an important therapeutic target with unmetmedical needs. The major goal in the treatment of posteriorsegments diseases is the delivery of therapeutic doses of drugsto the tissues while reducing the effects. Systems developed toachieve this goal range from simple solutions to novel drugdelivery systems, such as nanoparticles, liposomes, micelles,dendrimers, iontophoresis, and gene delivery systems [5–7].

2 The Scientific World Journal

Dendrimers are “tree-like,” nanostructured polymers thathave been interesting in terms of ocular drug delivery. Theyare attractive systems for drug delivery due to their nanosizerange, ability to display multiple surface groups that allowsfor targeting, and easy preparation and functionalization [8].Ongoing studies in developing improved ocular dendrimericsystems may not only serve to enhance the drug delivery tothe ocular surface, but also may provide effective delivery oftherapeutic agents to intraocular tissues, such as the retina orchoroid, using noninvasive delivery methods.

2. Challenges in Ocular Drug Delivery

Eye has a unique physical structure with protective barriers,which offers many challenges to the effective delivery ofdrugs to the eye. The eyeball is divided into 2 segments:the anterior segment containing the cornea, crystalline lens,iris, ciliary body, and fluid-filled aqueous humor and theposterior segment that includes the sclera, choroid vessels,retina, macula, optic nerve, and fluid-filled vitreous humor[2]. This organ is well protected with various specializedcellular modifications that give rise to various barriers thatpartially isolate the eye from the rest of the body, whichcan be a challenge for drug delivery [9]. These specialprocesses/barriers are as follows.

(i) The “inner and outer blood–retinal barriers” sepa-rate the retina and the vitreous from the systemiccirculation, and because of the absence of the cellularcomponents in vitreous body, it reduces convection ofmolecules [10].

(ii) The inner limiting membrane controls the exchangeand entry of particles from the vitreous to the retina.

(iii) The “blood-aqueous barrier” limits the transport ofmolecules from the blood to the inner part of the eye[11].

(iv) Intact structure of corneal epithelium with desmo-somes and tight junctions offers resistance to thepassage of most drugs due to the presence of lay-ers: hydrophobic epithelium, hydrophilic stroma, andhydrophobic endothelium [12].

(v) The tear film forms a mucoaqueous barrier thatcontinuously washes away the particles at the anteriorsurface of the eye [9].

The anatomical and physiological barriers mentionedabove are a challenge to ocular drug delivery. Solubility,lipophilicity, molecular size and shape, charge, and degreeof ionization of the drug also affect the penetration rateto the eye [13]. Drug delivery systems’ biocompatibility isalso relevant when ocular delivery is concerned. The specificchallenge of designing an ocular therapeutic system is toachieve an efficient concentration of the drug at the activesite for the duration to provide the therapeutic efficacy [14,15]. The requirements of an ideal topical formulation tothe eye must be fulfilled as follows: the formulation mustbe well tolerated and easy to administer; avoid systemicabsorption and increase drug retention time in the eye.

Various ophthalmic formulations have been developed toimprove ocular penetration, reduce toxicity, and improvetolerability [16, 17].

Typically “less than 5% of the topically applied drug”penetrates the cornea and reaches intraocular tissues, whilemost of the instilled dose is often absorbed systemically viathe nasolacrimal duct and conjunctiva [3]. The eye dropsare easy to instill but only a very small amount of theinstilled dose is absorbed into the target tissues. It becomesnecessary to apply large doses of drugs frequently to achievethe effective therapeutic dose which leads to an increase inboth local and systemic side effects [18]. Since the penetra-tion to cornea is often poor, either systemic or intravitrealadministration (injection or implant) is required in order totreat posterior segment diseases. Due to strong blood-oculartissue barrier, systemic administration requires large doses,while intravitreal injections and implants are very invasiveand are associated with a high degree of retinal damage risk,such as retinal detachment and endophthalmitis [19]. Thus,there has been growing attention to transscleral route in orderto deliver drug to the back of the eye [20]. Sclera is morepermeable than cornea and even it is highly permeable tothe large molecules of even protein size. However, it is morecomplicated to deliver the drug to retina, because in case oftransscleral application the drugmust pass across the choroidand retina pigment epithelium (RPE) [21].

The major goal is to develop suitable drug deliverysystems with improved bioavailability of drugs, increasedretention time, reduced side effects, cellular targeting, bet-ter patient compliance, and providing extended therapeuticeffects [22]. Currently, nanocarrier-based ocular drug deliv-ery systems including dendrimers appear to be the mostpromising way to meet the requirements of an ideal oculardrug delivery system.

3. Dendrimer Structure, Synthesis,and Properties

Dendrimers are monodisperse macromolecules with severalreactive end groups that surround a small molecule andform an internal cavity. Their tree-like branched architec-ture displaying a variety of controlled terminal groups isin particular very promising for biomedical applications[23]. Especially low generation dendrimers can encapsulatehydrophobic drug molecules into their internal cavities.Because of this unique structure, dendrimers are able tosolubilize poorly water-soluble drugs [24]. In addition to theextraordinary structural control, another outstanding featureof dendrimers is their actual mimicry of globular proteins.They are referred to as “artificial proteins,” based on theirsystematic, electrophoretic, dimensional length scaling andother biomimetic properties [25, 26].

Elements are added to dendrimer structure by a chemicalreaction series and build a branching spherical structure froma starting atom such as nitrogen. The central core moleculeshould have at least two reactive functional groups and therepeated branches are organized in a series of “radicallyconcentric layers” called “generations” [27]. A schematic

The Scientific World Journal 3

representation of a generation 2 dendrimer is given inFigure 1. Dendrimers are generally prepared using either adivergent method or a convergent one [28]. In the divergentmethod, dendrimer grows outwards from a multifunctionalcoremolecule. On the other hand, in the convergent approach,the dendrimer is constructed stepwise, starting from theend groups and progressing inwards. When the branchedpolymeric arms (dendrons) grew enough, they are attachedto a multifunctional core molecule [29]. A schematic repre-sentation of divergent and convergent methods, is given inFigure 2.Other approaches have been developed based on thedivergent and convergentmethods such as double exponentialgrowth, lego chemistry, and click chemistry. Preparation ofmonomers from a single starting material for both divergentand convergentmethods is possible using double exponentialgrowth approach.Then two result products are reacted to givea trimer, which can be used to repeat the growth again [30]. Inlego chemistry strategy, phosphorus dendrimers are preparedfrom highly functionalized cores and branched monomers.After several variations in general synthetic scheme, a schemeis developed that allows multiplications of the number ofterminal surface groups from “48 to 250” in one step [31].

Compared to other polymers, dendrimers have so manyadvantages such as their nanosize ranging from 1 to 100 nmwith lower polydispersity index that allows them to avoidRES uptake. Furthermore, targeting anywhere in the bodyis also possible, thanks to the multiple functional groupson their surface which makes it possible to attach vectordevices [32, 33]. Dendrimers have the ability to encapsu-late drug molecules into their internal cavities which leadsto enhanceed solubility, permeability, and retention effectdepending on their molecular weight. It was reported thatdrug absorption is increased with dendrimers association inthe cationic> uncharged> anionic order, where cationic den-drimers show permeation enhancement due to their abilityof interacting lipid bilayers. Smaller generation dendrimersalso have an enhancer effect on permeability since they havea better ability to move between cells [34].

Dendrimer cytotoxicity is related to the core chem-istry; the nature of the dendrimer surface is the mostinfluencing factor, because the interaction between surfacecationic charge of dendrimers and negatively charged bio-logical membranes is the main reason of toxicity. Lowergeneration dendrimers with anionic or neutral polar surfacegroups were reported to have higher biocompatibility ascompared to higher generation dendrimers with neutralapolar and cationic surface groups. It was reported thatfollowing repeated intravenous use or topical ocular appli-cation, dendrimers with cationic end groups are often toxic,whereas anionic dendrimers are not.Thus, in order to reducetoxicity, it is necessary to modify the surface amine groups ofthese dendrimers with neutral or anionic moieties [35–37].Recently, several studies have been published to report thatocular dendrimeric formulations were developed withoutcytotoxicity or irritation [38, 39]. For ocular drug delivery,it is very important to make sure that the dendrimers aresafe because serious side effects may occur due to cyto-toxicity at the ocular tissues. Safe dendrimer formulationsfor ocular drug delivery should have properties such as

Molecular cargo space

Core

Surface group

Branches

Figure 1: Schematic representation of a generation 2 dendrimer.

(A)

(B)

(a)(b)

2x (a) 3x (b)

16x8x4x

Figure 2: Schematic representation of divergent and convergentmethods: (A) the divergent growth method (B) the convergentgrowth method.

biocompatibility and low immunogenicity; thus they shouldbe carefully designed and evaluated. Furthermore, in order toovercome the potential toxicity of the dendrimers, it is veryimportant for ophthalmologists to participate and contributeto the scientific process alongside with chemists, formulationscientists and engineers.

4. Types of Dendrimers

The first “dendrimer family” that was synthesized, character-ized, and commercialized was poly(amidoamine) (PAMAM)dendrimers (Figure 3(a)) which were synthesized by the“divergent” method [25]. The structure of PAMAM den-drimers starts from an ammonia (NH

3) or ethylenediamine

(C2H8N2) molecule as a core that binds to the amine groups

of branches (R-NH2) and amide (–CONH

2R). Dendrimers

growth reaches a critical point where the branching armslimit their development into higher generations due to stericeffect that starts with G7. This effect decreases the syntheticyields of generations between G7 and G10 and prohibitsthe synthesis of any larger dendrimers [40, 41]. PAMAMdendrimers have a size range between 1.1 and 12.4 nm as theirgenerations grow through 1–10 [42]. These dimensions havebeen compared to proteins (3–8 nm), linear polymer-drugconjugates (5–20 nm), and viruses (25–240 nm). Overall,


H2N

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CH2H2NCH2CH2

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N

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(b)

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NH

HN

HNO

O O

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Core

NHNH2

NH2

NH2

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NH2

NH2

NH2

NH2

(d)

Figure 3: Structures of various types of dendrimers: (a) PAMAM dendrimer, (b) polypropyleneimine dendrimer, (c) polyaryl etherdendrimer, and (d) biodegradable polylysine dendron.

PAMAMdendrimers are considered as ideal carriers for drugdelivery due to their high aqueous solubility, large varietyof surface groups, and unique architecture. For medicalapplications, the most widely studied PAMAM dendrimershave been the derivatives with an −NH

2surface, a −COOH

surface, and an –OH surface [43].Poly(amidoamine) organosilicon (PAMAMOS) dendri-

mers are silicon containing first commercial dendrimerswhich are inverted unimolecular micelles that contain exte-rior hydrophobic organosilicon and interiorly hydrophilic,nucleophilic polyamidoamine [44].

Polypropyleneimine (PPI) dendrimers (Figure 3(b)) havebeen investigated for their medical applications, but it hasbeen shown that the presence of multiple cationic aminegroups causes significant toxicity. These dendrimers aregenerally poly-alkyl amines with primary amine end groupsand they are commercially available up to generation 5[45]. Polyaryl ether dendrimers (Figure 3(c)) also have beenevaluated for drug delivery, but it was found that it is requiredto use solubilizing groups at the periphery of them due totheir poor water solubility [46].

In addition, biodegradable dendrimers have beendesigned such as those based on polylysine (Figure 3(d)),poly(disulfide amine), polyether, or polyester and after

suitable surface modifications they have been developed aspromising antiviral, antibacterial, chemotherapeutic, andvaccine carrier candidates. Glycodendrimers, that includecarbohydrates in their architecture, also have great potentialas drug carriers.Most of the glycodendrimers have saccharideresidues on their outer surface, but glycodendrimerswith a sugar central core have also been described [47].Amino acid-based dendrimers, peptide dendrimers,hydrophobic dendrimers, and asymmetric dendrimers werealso investigated for a variety of pharmaceutical applications[30, 48].

Surface engineered dendrimers were developed as a strat-egy for abatement of dendrimer toxicity. Functionalizationhelps the dendrimers gain some beneficial properties fortheir use as a drug delivery system as well as reducing theinherent toxicity [37]. One of themost popular modificationsof dendrimer surface is PEGylation which offers so manyadvantages in addition to cytotoxicity reduction such asimproved bioavailability/oral delivery application related toimproved biodistribution and pharmacokinetics, enhancedsolubility, increase in drug loading, sustained and controlleddelivery of drugs, better transfection efficiency, and tumorlocalization [49]. Acetylation is another surface engineeringapproach to reduce toxicity based on modification of surfaceamino groups with acetyl groups [50].


(a) (b)

Figure 4: Schematic representation of drug encapsulated (a) and drug conjugated dendrimers (b).

There are already several dendrimer-based FDA-approved products in the market. For example, StratusCS Acute Care (Dade Behring), containing dendrimer-linked monoclonal antibody, was launched for “cardiacdiagnostic testing,” while another product based onmodified“Tomalia-type PAMAM” dendrimers, SuperFect (Qiagen),is a well-known gene transfection agent available for a widerange of cell lines [51, 52]. In addition, VivaGel, which is aformulation of “polyanionic lysine G4 dendrimers” with ananionic surface of “naphthalenedisulfonate (SPL7013) in aCarbopol gel” that shows antiviral activity against HIV andHSV for the treatment, has already been taken into clinicaltrials by Starpharma, according to FDA requirements. It iscurrently in Phase III clinical trials and it is also the subjectof a license agreement with Durex condoms for use as acondom coating [53, 54].

5. Interactions between Dendrimers andDrug Molecules

The dendrimer end group functionality can be modifiedto obtain molecules with novel biological properties suchas cooperative receptor-ligand interactions, which will helpdendrimers to interact with poorly soluble drugs. Den-drimers are able to increase the cellular uptake, bioavail-ability, and therapeutic efficacy, and they can also be usedto optimize the biodistribution and to reduce the systemictoxicity, clearance, and degradation rate drugs [55].

There are twomethods of dendrimer drug delivery: eitherlipophilic drugs can be encapsulated within the hydrophobicdendrimer cavity to make themwater soluble or drugs can becovalently attached onto the dendrimer surface. Encapsula-tion traps the drug inside the dendrimer using the interactionbetween drug and the dendrimer or the steric bulk of theexterior of the dendrimer. The nature of drug encapsulationmay be either a simple physical entrapment or can involvenonbonding-specific interactions within the dendrimer. Onthe other hand, the drug is attached to the exterior of

the dendrimer in dendrimer/drug conjugates. Conjugates areusually prodrugs that are either inactive or have decreasedactivity. The covalent conjugation of the drugs was mainlyused for targeting and achieving the higher drug payload,whereas the noncovalent interactions have resulted in highersolubility of insoluble drugs [23, 56]. A basic schematicrepresentation of drug encapsulated and drug conjugateddendrimers is given in Figure 4. The unique architecturalfeature of dendrimers and dendrons makes them also idealfor the construction of cross-linked covalent gels, and for theself-assembled noncovalent gels [57].

Drug dendrimer interactions are affected by the structure,generation, concentration, and surface engineering of thedendrimers. For example, PAMAM and PPI have a slightlydifferent dendritic framework. This difference in the internalbranchesmakes PPI dendrimers relativelymore hydrophobiccompared to PAMAM dendrimers and that results in dif-ferent solubilizing power [58]. Furthermore, modification ofdendrimer surface can improve the therapeutic efficacy ofdrugs in terms of targeting and reduced toxicity.

5.1. Encapsulation of Drugs within Dendritic Structure. Theacid-base reaction between the dendrimers and the guestmolecules such as drugs with coulomb attractions pulls theguest molecules inside the dendrimer structure, whereas thehydrogen bonding keeps them together.

Jansen and coworkers reported the first encapsulationof a dye inside a dendrimer in 1994, the so-called “dendritic box” [59]. Guest molecules could be entrapped inthe dendritic cavities during the synthetic process, withthe help of a shell preventing diffusion from the struc-tures, even after prolonged heating, sonication, or solventextraction [60, 61]. Following encapsulation of dyes todendrimers, anticancer drug encapsulation was the focusof the research. Kojima et al. encapsulated the anticancerdrugs methotrexate and doxorubicin using G3 and G4ethylenediamine-based poly(amidoamine) (PAMAM) den-drimers with poly(ethyleneglycol) monomethyl ether (M-PEG) grafts [62]. The same group also attached methotrexate


and folic acid to the exterior of the dendritic structure andtargeted the tumor cells using drug-dendrimer conjugates[63].

Dendrimers with an apolar core and polar shell have beenreferred to as “unimolecular micelles,” whereas the dendriticstructure is independent of dendrimer concentration unlikeconventional micelles [64]. However, this approach has adisadvantage that it is difficult to control the release ofdrugs from the dendrimer core. Poly(ethylene glycol) (PEG)has been used to modify dendrimers by conjugating PEGto the dendrimer surface to form a unimolecular micelleby providing a hydrophilic shell around the dendritic core.PEGylated dendrimers are of particular interest in drugdelivery because they are biocompatible and highly watersoluble and they have ability to modify the biodistribution ofcarrier systems [65, 66].

Zimmerman et al. synthesized “cored dendrimers” withmodified dendritic architecture to encapsulate the drug.Following the synthesis, the core was removed via cleavageof ester bonds, while the rest of the structure remained thesame as a consequence of robust ether linkages [67, 68].

“Dendrimeric block copolymers” have been synthesizedwith linear hydrophilic blocks and a hydrophobic dendriticblock and their ability to complex “poorly water solu-ble” molecules have been investigated. A series of “G1–G5PAMAM-block-PEG-block-PAMAM triblock copolymers”were synthesized by Kim et al. and studied as potentialpolymeric gene carrier [69].

Dendrimer-mediated complexation has advantages interms of stability, release control, high drug loading, andlower toxicity of entrapped drugs. However, the noncovalentcomplexation often leads to lower drug encapsulation andcomplex stability compared to covalent conjugation [70].

5.2. Dendrimer Drug Conjugation. The outer surfaces ofdendrimers have been investigated as potential interactionsites with drugs to increase the loading capacity. The numberof available surface groups for drug interactions increases intwofolds with each higher generation of dendrimer. Drugscan be conjugated to dendritic systems through ester, amide,or some other linkage depending on dendritic surface, whichcan be hydrolysed by endosomal or lysosomal enzymes,inside the cell [55, 56]. There are several ionizable groupson the surface of dendrimers, where ionizable drugs canattach electrostatically.Themain used points of attachment toconjugate drugs to dendrimers are amides, esters, disulfides,hydrazones, thiol-maleimide, and sulfinyl [43]. Many reportson drug loaded-dendrimers have shown that the release ofthe free drug can be enhanced by a suitable linker choice,especially, the linker/spacer length and flexibility. Some ofthe linkers are pH-sensitive and have proven to enhanceintracellular release of the free drug [71].

Patri et al. compared the covalently conjugated drug andnoncovalent inclusion complex in terms of release kineticsand efficacy, using generation 5 PAMAM dendrimers for tar-geting methotrexate. This study indicated that the inclusioncomplex releases the drug immediately and drug is active invitro, while covalently conjugated drug is better suited for

specifically targeted drug delivery [72]. A greater control overdrug release can be achieved by the covalent drug attach-ment using biodegradable linkages than electrostatic drugs-dendrimer complexes. However, the major disadvantage ofthe conjugation is the possibility of less active drug release ortoo slow drug liberation potential to be effective in vivo [73].

5.3. Dendritic Gels. Pharmaceutical applications of hydro-gels have attracted attention because of their architecturalproperties, drug loading capacity, and controlled drug releasecapability. Hydrogels are hydrophilic and “three-dimensionalpolymeric networks” have found application in drug deliverydue to their high water absorbing capacity [74]. “In situ form-ing gels” have been investigated for a variety of applicationsincluding ocular, oral, nasal, vaginal, rectal, and injectable.[75, 76]. Dendrimers and dendrons’ can be prepared withcontrolled molecular sizes due to their dendritic structureand their nature is between traditional gel polymers and theorganic compounds with low molecular weight used in the“self assembled supramolecular gels” [57].

A “polymer network” is usually obtained with the use ofa crosslinker during polymerization. Synthesis of hydrogelshas been a function of themultivalent crosslinker behavior ofdendriticmolecules [77]. It has been shown that the dendriticbranching has an important role in the self-assembly control.Furthermore, the repeated use of its key structural motifscan lead to multiple interactions between branched units andstrengthen the noncovalent interactions responsible for the“self-assembly process” [78].

6. Ocular Applications of Dendrimeric DrugDelivery Systems

Dendrimers have been investigated for ophthalmic drugdelivery since it offers a number of advantages as a carriersystem. It has been reported that dendrimers were usedfor several purposes such as drug delivery, gene delivery,antioxidant delivery, peptide delivery, biomedical imaging,and genetic testing in ophthalmology [79]. A list of the ocularapplications of dendrimers is given in Table 1.

Dendrimers are able to transport into and out of the cells.PAMAM dendrimers can have different cell entry pathways,depending on the functional groups on the surface. AnionicPAMAM dendrimers are endocytosed primarily througha caveolin-mediated process, whereas neutral and cationicdendrimers are internalizated in cells following a clathrin-mediated process. These pathways can be highly beneficial inthe case of crossing the epithelial and retinal barriers in thecornea and retina [80, 81].

Different ocular application routes have been success-fully used for dendrimeric drug delivery and better watersolubility, permeability, bioavailability, and biocompatibilityhave been reported. Vandamme and Brobeck have evaluatedseveral series of poly(amidoamine) (PAMAM) dendrimersfor controlled ocular drug delivery and residence time ofpilocarpine nitrate and tropicamide was found to be longerfor the anionic dendrimer solutions. Results of a “mioticactivity test” on albino rabbits showed that these PAMAM

The Scientific World Journal 7Ta

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formulations improved pilocarpine nitrate bioavailabilitycompared to the control and also prolonged the reduction ofintraocular pressure (IOP), indicating increased precornealresidence time [82].

Durairaj et al. investigated dendrimeric polyguanidily-ated translocators (DPTs), which are a class of dendrimerswith tritolyl branches and surface guanidine groups as poten-tial ophthalmic carriers for gatifloxacin, a “fourth generationfluoroquinolone” approved for conjunctivitis treatment. Theresults have indicated that the DPT forms stable gatifloxacincomplexes and enhances solubility, permeability, anti-MRSAactivity, and in vivo delivery of gatifloxacin and seems like apotential delivery system allowing once a day dosing [84].

“Phosphorus containing dendrimers,” with one quater-nary ammonium salt as core and several carboxylic acidterminal groups have been synthesized from generation 0to generation 2 by Spataro et al. These dendrimers havebeen tested in vivo in a rabbit model to evaluate ocularcarteolol delivery and an increase of the carteolol amount inthe aqueous humour is observed. No irritation was observed,even several hours after cationic dendrimers were applied[83].

Shaunak et al. have synthesized water soluble conjugatesof D(+)-glucosamine and D(+)-glucosamine 6-sulfate withanionic PAMAM (G3.5) dendrimers to obtain synergistic“immunomodulatory and antiangiogenic effect.” When den-drimer glucosamine and dendrimer glucosamine 6-sulfateconjugates were used together in a clinically relevant scar tis-sue formation rabbit model after glaucoma filtration surgery,it has been shown that the long-term success of the surgeryhas increased from 30% to 80%. Furthermore, neither micro-bial infections nor clinical, biochemical, or hematologicaltoxicity was observed in all animals [38].

Intraocular tumors such as retinoblastoma present a highrisk of complications with high metastatic potential. One ofthe limited studies that have been done for drug deliveryto intraocular tumors has explored the use of PAMAMdendrimers with carboxyl end groups (G3.5-COOH) forextended half life and sustained delivery of carboplatin withlowered therapeutic toxicity. Carboplatin-loaded PAMAMdendrimer complexes were explored in a transgenic murineretinoblastoma model, following subconjunctival adminis-tration. It was reported that the carboplatin-loaded den-drimer nanoparticles not only crossed the sclera, but werealso retained for an extended period of time in the tumorvasculature, providing a sustained treatment effect [39].

In another research, biocompatible conjugates oflipophilic amino-acid dendrimers have been developed withcollagen scaffolds to obtain better physical and mechanicalproperties and adhesion ability. Dendrimers-based approachwas used for antivascular endothelial growth factoroligonucleotide (VEGF-ODN) delivery and successfullytested in a rat model to treat choroidal neovascularization(CNV). The results indicated that dendrimer/ODN-1complexes significantly suppressed VEGF expression in celllevel studies around 40 to 60%. Examinations of injectedrat eyes also showed that no significant toxicity and damagewere caused by the complex injections [85].

The repair of wounds such as corneal wounds that arisefrom surgical procedures has a significant importance forclinical aspects and research. Therefore, Duan and cowork-ers have generated highly crosslinked collagen using G2polypropyleneimine octaamine dendrimers to use it as atissue-engineering corneal scaffold. The optical transparen-cies of the dendrimer crosslinked collagen, EDC (1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride),and glutaraldehyde crosslinked collagen thermal gels werecompared and the transparency of dendrimer crosslinkedcollagen was found to be significantly higher. Results haveshown that dendrimer crosslinked collagen gels improved“human corneal epithelial cell growth” and adhesion withoutcell toxicity [86]. The same group conjugated the “surfacemodified dendrimers” with cell adhesion peptides to beused as corneal tissue engineering scaffolds and the materialhas been incorporated into both bulk structures of the gelsand onto the gel surface. Dendrimer amine groups weremodified using carboxyl group and it was found that thesurface modification promoted human corneal epithelial celladhesion and proliferation [87].

Grinstaff has developed a series of dendrimeric adhesives,to repair corneal wounds, composed of generations 1, 2,and 3 (G1, G2, and G3) combined with PEG, glycerol, andsuccinic acid. The polymer was modified to contain ter-minal methacrylate groups, ([G1]-PGLSA-MA)

2-PEG. Two

strategies have been explored to form the ocular adhesives:a photocrosslinking reaction and a peptide ligation reactionto couple the individual dendrimers together. It was reportedthat both hydrogels were adhesive, elastic, soft, transparent,and hydrophilic. The in vivo studies in chicken eyes haveindicated that the photocrosslinkable ([G1]-PGLSA-MA)

2-

PEG adhesive completely sealed on postoperative day. Thehistological studies have also demonstrated that woundssealed using these adhesive gels appeared to be more com-plete after 28 days as compared to sutured wounds. Theadvantage of photo-cross-linked gels is the light-inducedability of the polymer to crosslink and adhere to the tissue;however, there is a potential risk of ocular damagewhenusinglight [88].

Photodynamic therapy is a potentially efficient treat-ment for retinoblastoma along with the other varioussolid tumours. Makky et al. have designed a photosensi-tizer, porphyrin-based glycodendrimers with the mannose-specific ligand protein Concanavalin A conjugated on totheir surface, to specifically target the tumor cells in theretina. It was reported that the mannosylated dendrimersdemonstrated specific interactions with the receptors in thelipid bilayer and accumulation in malignant ocular tissuewas enhanced [90]. Dendrimers have also been exploredas drug carriers and photosensitizers for exudative age-related macular degeneration (AMD) and CNV treatment.Nishiyama et al. investigated porphyrin-based dendrimersfor their efficacy in treating retinal tumors and exudativeAMD associated with CNV. The formulations showed selec-tive accumulation within 24 h in the CNV lesions wheninjected into a CNV rat model [91, 92]. The same groupdeveloped phthalocyanine core-based dendrimer photosen-sitizers, which can be used to compact and deliver therapeutic


genes with a targeting approach. Transgene expression wasmonitored only in the irradiated areas upon subconjunctivalinjection of the dendrimer formulation and followed by laserirradiation [93].

Sugisaki et al. investigated the accumulation of den-drimer porphyrin (DP), DP encapsulated polymericmicelles,and the efficacy of photodynamic therapy (PDT) using acorneal neovascularization model in mice. In this study a3rd generation “aryl ether dendrimer zinc porphyrin” withcarboxyl ending groups and polymeric micelles composedof the DP and PEG-poly(L-lysine) was used for PDT as aphotosensitizer formulation. The results showed that follow-ing administration, in 1 hour to 24 hours, both DP and DP-micelle were accumulated in the neovascularized area [89].

Bravo-Osuna and coworkers investigated the in vitroand in vivo tolerance of carbosilane dendrimers (G1 andG3, anionic and cationic) for topical ophthalmic adminis-tration. Formulations were applied to New Zealand albinorabbits and it was reported that animals did not presenteither discomfort or clinical signs after the administrationof dendrimer solutions. Nonionic interactions via hydrogenbonding between the PAMAM dendrimer surface moietiesandmucins were observed.MTT test results also showed thatanionic dendrimers were nontoxic for both conjunctival andcorneal cells [94].

In a recent study, Puerarin–dendrimer complexes wereprepared using PAMAM dendrimers (G3.5, G4, G4.5, andG5) and their physicochemical properties, in vitro release,corneal permeation, and ocular residence times were deter-mined. Valia-Chien evaluated the corneal permeation andocular residence time in rabbits using diffusion cells withexcised corneas. It was reported that puerarin-dendrimercomplexes exhibited longer residence time in rabbit eyes thanpuerarin eye drops, without damage to the corneal epitheliumor endothelium. Also results of the in vitro release studiesshowed that puerarin release was much more slower fromcomplexes than the free puerarin in PBS. However, cornealpermeation studies suggested that there was no significantdifference between puerarin-dendrimer complexes and puer-arin eye drops on drug permeability coefficient [95].

Targeted drug therapy for retinal neuroinflammationwas explored using “G4.0 hydroxyl-terminated PAMAMdendrimer-drug conjugate nanodevices” by Iezzi et al. Fluo-cinolone acetonide was conjugated to the dendrimers and invivo efficacy was assessed for over a 4-week period, using the“Royal College of Surgeons rat retinal degenerationmodel.” Itwas reported that upon intravitreal administration PAMAMdendrimers were selectively localized within “activated outerretinal microglia” in two retinal degeneration rat models andthe dendrimers were detected in the target cells, even 35 daysafter administration [96].

A PAMAM dendrimer hydrogel has been developed byHolden and coworkers that is made from “ultraviolet-curedPAMAMdendrimer” linkedwith PEG-acrylate chains for thedelivery of two antiglaucoma drugs which were brimonidine(0.1% w/v) and timolol maleate (0.5% w/v). Dendrimerichydrogel was obtained by crosslinking of the reactive acrylategroups, triggered by UV light. It was reported that thedendrimeric hydrogel was mucoadhesive and nontoxic to

epithelial cells of human cornea. Higher uptake from “humancorneal epithelial cells” and significantly enhanced “bovinecorneal transport” were reported for both drugs, comparedto the eye drops. The higher uptake in the dendrimerichydrogel formulations explained the temporary decomposi-tion of the corneal epithelial tight junctions [97]. The samegroup also developed a novel “hybrid PAMAM dendrimerhydrogel/poly(lactic-co-glycolic acid) (PLGA) nanoparticleplatform (HDNP)”, again for codelivery of brimonidine andtimolol maleate. The formulations were also evaluated interms of their in vitro potential toxicity and it was found thatthe formulation was noncytotoxic to human corneal epithe-lial cells. Following topical administration of the HDNP inadult “normotensive Dutch-beltedmale rabbits,” formulationwas found to be effective and maintained significantly higherconcentrations of both drugs up to 7 days in aqueous humorand cornea compared to saline. Furthermore, it was reportedthat dendrimeric hydrogel and PLGA nanoparticles were notinducing any ocular inflammation or discomfort. This studydemonstrated that this new formulation is able to enhancedrug bioavailability, and following topical administration,it is capable of sustaining drug activity [98]. Wathier andcoworkers also developed an in situ gel formulation usingLsyxCysy dendritic polymers to be used in cataract incisionsinstead of nylon sutures. It was reported that the hydrogelsealant procedure was simple and required less surgical timethan conventional suturing and no additional tissue traumawas inflicted [99].

7. Conclusion

Effective treatment of ocular diseases is still a challenge inpharmaceutical research, because of the unique physiologyof eye and presence of the ocular barriers especially inposterior segments of the eye. Research in ophthalmic drugdelivery during the last two decades has undergone majoradvancements from the use of conventional formulationssuch as solutions, suspensions, and ointments to viscosity-enhancing in situ gel systems, different inserts, colloidalsystems, and so forth.

Given their structural features,most of the ocular diseaseswould benefit from long-lasting drug delivery of dendrimersand dendrimer-based drug delivery systems. It was alreadyreported that dendrimers present practical solutions to drugdelivery issues such as solubility, biodistribution, and target-ing. Since it is easy to control the features of dendrimers suchas their size, shape, generation, branching length, molecularsize, and surface functionality, these compounds are idealcarriers in pharmaceutical applications. Recent researcheshave shown that dendrimers are able to

(i) enhance the corneal residence time of drugs admin-istered topically,

(ii) target retinal neuroinflammation and provide tar-geted, sustained neuroprotection in retinal degener-ation,

(iii) deliver drugs to the retina upon systemic administra-tion,


(iv) be effective as corneal glues to potentially replacesutures following corneal surgeries.

Even though dendrimers are not approved yet for clinicaluse in the eye, their promising preclinical results can providesignificant opportunities.

Conflict of Interests

The authors would like to declare that they have no conflictof interests and have received no payment in the preparationof this paper.

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